Wodicka Lisa M, Ciceri Pietro, Davis Mindy I, Hunt Jeremy P, Floyd Mark, Salerno Sara, Hua Xuequn H, Ford Julia M, Armstrong Robert C, Zarrinkar Patrick P, Treiber Daniel K
Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, CA 92121, USA.
Chem Biol. 2010 Nov 24;17(11):1241-9. doi: 10.1016/j.chembiol.2010.09.010.
Interactions between kinases and small molecule inhibitors can be activation state dependent. A detailed understanding of inhibitor binding therefore requires characterizing interactions across multiple activation states. We have systematically explored the effects of ABL1 activation loop phosphorylation and PDGFR family autoinhibitory juxtamembrane domain docking on inhibitor binding affinity. For a diverse compound set, the affinity patterns correctly classify inhibitors as having type I or type II binding modes, and we show that juxtamembrane domain docking can have dramatic negative effects on inhibitor affinity. The results have allowed us to associate ligand-induced conformational changes observed in cocrystal structures with specific energetic costs. The approach we describe enables investigation of the complex relationship between kinase activation state and compound binding affinity and should facilitate strategic inhibitor design.
激酶与小分子抑制剂之间的相互作用可能取决于激活状态。因此，要详细了解抑制剂结合情况，就需要对多种激活状态下的相互作用进行表征。我们系统地研究了ABL1激活环磷酸化和PDGFR家族自抑制近膜结构域对接对抑制剂结合亲和力的影响。对于一组多样化的化合物，亲和力模式能正确地将抑制剂分类为具有I型或II型结合模式，并且我们表明近膜结构域对接会对抑制剂亲和力产生显著的负面影响。这些结果使我们能够将共晶体结构中观察到的配体诱导的构象变化与特定的能量代价联系起来。我们所描述的方法能够研究激酶激活状态与化合物结合亲和力之间的复杂关系，并且应该有助于进行策略性的抑制剂设计。
